3rkz

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==Discovery of a stable macrocyclic o-aminobenzamide Hsp90 inhibitor capable of significantly decreasing tumor volume in a mouse xenograft model.==
==Discovery of a stable macrocyclic o-aminobenzamide Hsp90 inhibitor capable of significantly decreasing tumor volume in a mouse xenograft model.==
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<StructureSection load='3rkz' size='340' side='right' caption='[[3rkz]], [[Resolution|resolution]] 1.57&Aring;' scene=''>
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<StructureSection load='3rkz' size='340' side='right'caption='[[3rkz]], [[Resolution|resolution]] 1.57&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
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<table><tr><td colspan='2'>[[3rkz]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3RKZ OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3RKZ FirstGlance]. <br>
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<table><tr><td colspan='2'>[[3rkz]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3RKZ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3RKZ FirstGlance]. <br>
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</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=06T:(5R,6S)-3-(L-ALANYL)-5,6,15,15,18-PENTAMETHYL-17-OXO-2,3,4,5,6,7,14,15,16,17-DECAHYDRO-1H-12,8-(METHENO)[1,5,9]TRIAZACYCLOTETRADECINO[1,2-A]INDOLE-9-CARBOXAMIDE'>06T</scene></td></tr>
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</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.5693&#8491;</td></tr>
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<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">HSP90A, HSP90AA1, HSPC1, HSPCA ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
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<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=06T:(5R,6S)-3-(L-ALANYL)-5,6,15,15,18-PENTAMETHYL-17-OXO-2,3,4,5,6,7,14,15,16,17-DECAHYDRO-1H-12,8-(METHENO)[1,5,9]TRIAZACYCLOTETRADECINO[1,2-A]INDOLE-9-CARBOXAMIDE'>06T</scene></td></tr>
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3rkz FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3rkz OCA], [http://pdbe.org/3rkz PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=3rkz RCSB], [http://www.ebi.ac.uk/pdbsum/3rkz PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=3rkz ProSAT]</span></td></tr>
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=3rkz FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3rkz OCA], [https://pdbe.org/3rkz PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3rkz RCSB], [https://www.ebi.ac.uk/pdbsum/3rkz PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3rkz ProSAT]</span></td></tr>
</table>
</table>
== Function ==
== Function ==
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[[http://www.uniprot.org/uniprot/HS90A_HUMAN HS90A_HUMAN]] Molecular chaperone that promotes the maturation, structural maintenance and proper regulation of specific target proteins involved for instance in cell cycle control and signal transduction. Undergoes a functional cycle that is linked to its ATPase activity. This cycle probably induces conformational changes in the client proteins, thereby causing their activation. Interacts dynamically with various co-chaperones that modulate its substrate recognition, ATPase cycle and chaperone function.<ref>PMID:15937123</ref> <ref>PMID:11274138</ref>
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[https://www.uniprot.org/uniprot/HS90A_HUMAN HS90A_HUMAN] Molecular chaperone that promotes the maturation, structural maintenance and proper regulation of specific target proteins involved for instance in cell cycle control and signal transduction. Undergoes a functional cycle that is linked to its ATPase activity. This cycle probably induces conformational changes in the client proteins, thereby causing their activation. Interacts dynamically with various co-chaperones that modulate its substrate recognition, ATPase cycle and chaperone function.<ref>PMID:15937123</ref> <ref>PMID:11274138</ref>
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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An extension of our previously reported series of macrocyclic ortho-aminobenzamide Hsp90 inhibitors is reported. Addition of a second methyl group to the tether provided analogs that show increased potency in binding as well as cell-proliferation assays and, more importantly, are stable toward microsomes. We wish to disclose the discovery of a macrocycle which showed impressive biomarker activity 24-h post dosing and which demonstrated prolonged exposure in tumors. When studied in a lung cancer xenograft model, the compound demonstrated significant tumor size reduction.
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Discovery of a stable macrocyclic o-aminobenzamide Hsp90 inhibitor which significantly decreases tumor volume in a mouse xenograft model.,Zapf CW, Bloom JD, Li Z, Dushin RG, Nittoli T, Otteng M, Nikitenko A, Golas JM, Liu H, Lucas J, Boschelli F, Vogan E, Olland A, Johnson M, Levin JI Bioorg Med Chem Lett. 2011 Jun 27. PMID:21715165<ref>PMID:21715165</ref>
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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</div>
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<div class="pdbe-citations 3rkz" style="background-color:#fffaf0;"></div>
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==See Also==
==See Also==
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*[[Heat Shock Proteins|Heat Shock Proteins]]
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*[[Heat Shock Protein structures|Heat Shock Protein structures]]
== References ==
== References ==
<references/>
<references/>
__TOC__
__TOC__
</StructureSection>
</StructureSection>
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[[Category: Human]]
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[[Category: Homo sapiens]]
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[[Category: Bloom, J D]]
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[[Category: Large Structures]]
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[[Category: Boschelli, F]]
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[[Category: Bloom JD]]
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[[Category: Dushin, R G]]
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[[Category: Boschelli F]]
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[[Category: Golas, J M]]
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[[Category: Dushin RG]]
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[[Category: Johnson, M]]
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[[Category: Golas JM]]
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[[Category: Levin, J I]]
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[[Category: Johnson M]]
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[[Category: Li, Z]]
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[[Category: Levin JI]]
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[[Category: Liu, H]]
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[[Category: Li Z]]
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[[Category: Lucas, J]]
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[[Category: Liu H]]
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[[Category: Nikitenko, A]]
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[[Category: Lucas J]]
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[[Category: Nittoli, T]]
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[[Category: Nikitenko A]]
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[[Category: Olland, A]]
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[[Category: Nittoli T]]
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[[Category: Otteng, M]]
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[[Category: Olland A]]
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[[Category: Vogan, E]]
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[[Category: Otteng M]]
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[[Category: Zapf, C W]]
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[[Category: Vogan E]]
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[[Category: Atp binding domain]]
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[[Category: Zapf CW]]
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[[Category: Atp-binding]]
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[[Category: Chaperone]]
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[[Category: Chaperone-chaperone inhibitor complex]]
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[[Category: Nucleotide-binding]]
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[[Category: Phosphoprotein]]
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[[Category: Stress response]]
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Current revision

Discovery of a stable macrocyclic o-aminobenzamide Hsp90 inhibitor capable of significantly decreasing tumor volume in a mouse xenograft model.

PDB ID 3rkz

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